Transmission electron microscopy (EM) is used as an adjunct procedure in the diagnosis of a wide range of neoplastic and non neoplastic diseases and can be extremely useful in well chosen diagnostic dilemmas. The service is regularly inspected and certified by CAP, and is the only diagnostic CAP-certified EM service on NIH campus. A total of 113 cases were processed last year, some consisting of more than one specimen and some requiring evaluation and diagnosis in a less than 24 hour period (e.g. renal biopsies from patients on renal transplant protocols). In addition, 240 research specimens were also processed and evaluated to support experimental studies of various NCI/NIH investigators. The diagnostic specimens that are submitted to our service for ultrastructural evaluation come from patients treated in NCI/NIH protocols and are diagnostically and scientifically challenging. Due to the nature of the NCI protocols, we are often the first to describe the unusual and unique ultrastructural findings of a tumor or disease, or the outcome of experimental treatments, as demonstrated in the following examples: )(1) We showed for the first time that asymptomatic "mesenchymal tumorlets" arising in the spinal cord and nerve root tissue of VHL patients, consist not only of poorly differentiated mesenchymal cells, but also of a few "stromal" cells with abundant cytoplasmic vacuolization similar to those seen in well developed hemangioblastomas., thus confirming their histogenetic relationship. (2) EM demonstrated intracellular accumulation of bacteria in HeLa cells overexpressing bacteria-binding receptors CLA-1 and CLA-2. This novel finding has important clinical implications, because it shows that these receptors may either facilitate infection or represent a mechanism of bacterial internalization and degradation and thereore, may be potential targets for therapeutic intervention in infectious diseases (Vishnyakova TG, et al: Proc Natl Acad Sci, in press). (3) In collaboration with Dr. Schiffman and Quezado, we helped describe the effects of enzyme replacement therapy in a patient with Fabry disease (reference below). We found that repeated infusions of the replacement enzyme over a prolonged period do not clear storage material in cells other than vascular endothelial cells, and this may constitute a significant limitation of this therapeutic approach in patients with Fabry disease. (4) EM findings were instrumental in the characterization of a novel form of leukodystrophy associated with hypogonadotropic hypogonadism. A particularly distinguishing novel feature was our finding of myelin sheath abnormalities and cholesterol crystal accumulation in Schwann cells of a peripheral sural nerve biopsy, which led to the study and subsequent identification of abnormal lipid composition in sural nerve biopsies from 3 similar patients, thus supporting a demyelinating process (Timmons M et al. Neurology, in press. (5) In collaboration with Dr. Mattes, we have shown that the CD20 and HLA-DR antibodies, which are used in the treatment of lymphomas, when bound to a B-lymphoma cell line are incorporated into a conglomerate of vesicles, which are shed from the surface of the lymphoma cells by a cytoplasmic pinched-off mechanism. This process, if it occurs in vivo, may affect the therapeutic efficacy of these antibodies (Michel RB et al. Leukemia and Lymphoma, in press. (6) We contributed to the characterization of the bilateral massive macronodular adrenocortical disease in a patient with hereditary leiomyomatosis.